The invention relates to agents containing at least one compound having antiprogestational activity (AG) and at least one compound having anti-estrogenic activity (AE). The invention concerns, in particular, agents of the indicated type for induction of labor and for termination of pregnancy, as well as for the treatment of gynecological disorders. The invention also relates to the use of a combination of AG with AE for the above-mentioned indications.
In order to avert danger to mother and/or child, it is sometimes necessary to induce labor artificially or to terminate a pregnancy prematurely. For this purpose, surgical techniques and pharmacological methods are available.
A possible pharmacological method is vaginal or intramuscular administration of prostaglandins which is used in case of terminating a pregnancy in the first or second trimester of pregnancy (Contraception 1983, 27 : 51-60 and Int. J. Gynaecol. Obstet. 1982, 20 : 383-386).
The advantage inherent in using prostaglandins is the possibility of utilizing them over a long time period of pregnancy. Disadvantages of the prostaglandins are acute side effects, such as pain and nausea. Besides, the success rate in case of termination of pregnancy in advanced stages of pregnancy is no more than 90% even with a prolonged duration of prostaglandin treatment.
Another possibility of terminating pregnancy resides in the administration of an antigestagen (Med. et Hyg. 1982, 40 : 2087-2093). Antigestagens are more compatible than prostaglandins, but they have lower efficacy, higher latency and individual variability of onset of activity as compared with the prostaglandins. Besides, it has been observed in the clinic that they exhibit tendency toward, in part, severe hemorrhages.
The combined use of prostaglandins and antigestagens (U.S. Pat. No. 4,626,531, issued on Dec. 2, 1986), although affording irrefutable advantages over the sole administration of the individual active agents (above all, reduction of the respective quantity of active ingredient), does not solve the problems, for example, which occur generally with the use of prostaglandins. These problems include undesirable side effects, such as gastrointestinal effects or pain in the uterus. In addition, treatment must take place on an inpatient basis; moreover, storage and shelf life of the drug are limited and/or expensive because of their lack of stability; and the most user-friendly form of administration, namely oral, is impossible. Thus,-it is likewise impossible to combine both active agents in a tablet, pill, or dragee.
Pharmaceutical compositions for postcoital fertility control, containing a competitive progesterone antagonist (antigestagen) as well as a progesterone and estrogen synthesis blocker, have been described in U.S. Pat. No. 4,670,426. Typical representatives for the competitive progesterone antagonist to be used which are mentioned are fluocinolone acetonide, triamcinolone acetonide, steroids having a cyclic 16, 17-acetal with acetone and 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl-1)-17.alpha.-prop-1-ynyl) estra-4, 9-dien-3-one, and equivalent derivatives. The typical content ranges between 20 and 50 mg. Examples cited for the progesterone and estrogen synthesis blocker are aminoglutethimide, 2.alpha.-cyano-4, 4, 117.alpha.-trimethyl-5-androst-5-en-17.beta.-ol-3-one, 20, 25-diazocholesterol, and compounds having equivalent activity, namely in a dosage of 300-1,000 mg. The use of the composition, according to U.S. Pat. No. 4,670,426 must take place maximally early within the first week after sexual intercourse over a time period of 3 days; most advantageously, treatment should be continued for 2-6 days. The prevention of nidation and thus pregnancy is brought about by the synergistic effect in the combined use of the two components of the composition, namely with a success rate on the order of magnitude of 90% or thereabove. See also commonly assigned U.S. Ser. No. 206,750 of Jun. 15, 1988.
For induction of labor, termination of pregnancy, and treatment of gynecological disorders, compounds having anti-estrogenic activity have not been proposed heretofore.